1. Field of the Invention
This invention relates to a probe carrier carrying a probe rigidly secured thereto for detecting a target substance. The present invention also relates to a method of manufacturing such a probe carrier.
2. Related Background Art
When analyzing the base sequence of a gene DNA or conducting a gene diagnosis by analyzing a number of items simultaneously, probes of different types are needed to single out a DNA having a target base sequence in order to raise the reliability of operation. DNA microchips have been attracting attention as means for providing probes of a number of different types to be used for such sorting operations. A large number of solution species (e.g., 96, 384 or 1,536 species) containing proteins or drugs to be sorted normally have to be subjected to a screening operation in an orderly manner in the field of high throughput screening of chemicals or combinatorial chemistry. For these purposes, techniques of sequentially arranging a large number of different types of drugs, automatic screening technologies and dedicated devices for sorting the drugs arranged in this way and software for controlling a number of screening operations and statistically processing the obtained results have been and are being developed.
Basically, such screening operations as described above that are conducted in parallel simultaneously consist of detecting an action or non-action or a response or non-response of each specimen to the known probes arranged in array, or probe array, provided as means for sorting the substances of specimens for evaluation under the same conditions. Generally, the action or response to be used with each probe is defined in advance and therefore substances of the same type are normally used as probe species that are mounted on a probe array. Then, the probe array may be that of DNA probes carrying a group of DNAs having different respective base sequences. DNAs, proteins and synthesized chemicals (drugs) are examples of substances that may be used for a group of probes. While a probe array of a group of a plurality of probe species is used in many instances, a large number of identical DNAs having the same base sequence, identical proteins having the same amino acid sequence or identical chemical substances may be arranged in an array. Such probes are mainly used for screening drugs. If the target substance is a nucleic acid, the probes may be formed by using a single stranded nucleic acid that shows a complementary sequence relative to all or a part of the target nucleic acid and is adapted to a specific hybridization with the base sequence of the target nucleic acid.
In a probe array formed by a plurality of probe species, a group of DNAs having different base sequences, a group of proteins having different amino acid sequences, a group of different chemical substances or the like are often arranged in an array on a substrate according to a predetermined sequence of arrangement. Particularly, DNA probe arrays are used for analyzing the base sequence of a gene DNA or conducting a gene diagnosis by analyzing a number of items simultaneously in order to raise the reliability of operation as pointed out above.
U.S. Pat. No. 5,424,186 describes a technique of preparing an array of DNA probes with DNAs having respective base sequences that are different from each other by means of a stepwise elongation reaction conducted on a carrier by utilizing photodecomposable protective groups and photolithography. With the proposed technique, it is possible to prepare a DNA probe array carrying DNAs of more than 10,000 different kinds that are different from each other in terms of a base sequence per 1 cm2. The process of synthesizing a DNA by means of a stepwise elongation reaction, using this technique, comprises a photolithography step in which dedicated photomasks are used respectively for the four different kinds of bases (A, T, C, G) in order to selectively elongate any of the bases at a predetermined position of the array so that consequently DNAs of different species having desired respective base sequences are synthetically produced and arranged on a substrate in a predetermined order.
Besides the above-described technique, techniques of manufacturing a probe array by synthesizing DNAs for probes in advance in a refined manner, confirming, if necessary, their respective base lengths and supplying the DNAs to a substrate by means of an appropriate device such as a microdispenser are known. PCT Patent Publication WO 95/35505 describes a technique of supplying DNAs onto a membrane by means of capillaries. With this technique, it is theoretically possible to manufacture about 1,000 DNA arrays per 1 cm2. It is basically a technique of manufacturing a probe array by supplying a probe solution to a predetermined position of a substrate for each probe by means of a capillary-shaped dispensing device and repeating this operation.
There are also known techniques of supplying a solution of a substance necessary for conducting an operation of DNA solid phase synthesis on a substrate in each elongation step. For example, European Patent Publication EP 0703825B1 describes a technique of synthesizing DNAs of a plurality of different species having respective predetermined base sequences in a solid phase by supplying nucleotide monomers and activators by means of respective piezo jet nozzles for the purpose of solid phase synthesis of DNAs. This supply (application) technique utilizing an ink-jet method is reliable in terms of reproducibility of the supply rate if compared with a solution supply (application) technique utilizing capillaries and also provides advantages for realizing high density probe arrays because the nozzle structure of the ink-jet system can be miniaturized.
Patent Publication EP 895082 discloses a technique of causing a liquid containing a probe to adhere to a solid phase as liquid droplets by means of a bubble jet head and forming a spot containing a probe on the solid phase. Patent Publication WO 00/53736 discloses a method of manufacturing arrays by immobilizing a nucleic acid in a hollow thread.
Thus, it is the object of the present invention to provide a probe carrier that is adapted to mass production and a method of manufacturing such a probe carrier.